DESCRIPTION (Adapted from the applicant's description) Cortistatin is a novel neuropeptide that has a strong similarity to somatostatin and selectively induces slow wave sleep, presumably by antagonizing the effects of the neurotransmitter acetylcholine on cortical excitability. Preprocortistatin is exclusively expressed in a subset of cortical and hippocampal interneurons that utilize GABA as their neurotransmitter. Total sleep deprivation increases the steady state levels of preprocortistatin mRNA up to four fold. Pharmacological, molecular, genetic, physiological and behavioral methods will be used to determine the role of cortistatin in sleep. This proposal will investigate whether the effects of cortistatin on sleep are dependent on the levels of cortical arousal and on circadian rhythms. The structural requirements for cortistatin's selective effect on slow-wave sleep will also be investigated. We will determine how sleep deprivation, circadian rhythms and age affect preprocortistatin mRNA expression. Finally, to unequivocally establish cortistatin as a sleep factor, we will generate mice that are deficient in cortistatin. The effects of cortistatin deficiency will be analyzed in terms of the electrophysiological and behavioral properties of cortistatin knock-out mice. These mice may also serve as a mouse model for sleep disorders. These studies will give insight into the function of cortistatin in sleep and may yield therapeutic applications and a better understanding of human sleep disorders in which cortical activity is affected.